rs12210123

Positions:

• chr6-70300398-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000357250.11(COL9A1):​c.89-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,544,692 control chromosomes in the GnomAD database, including 26,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3338 hom., cov: 31)
  • Exomes 𝑓: 0.18 (23582 hom.)
• Consequence: COL9A1 ENST00000357250.11 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005395
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.450

Genes affected

COL9A1 (HGNC:2217): (collagen type IX alpha 1 chain) This gene encodes one of the three alpha chains of type IX collagen, which is a minor (5-20%) collagen component of hyaline cartilage. Type IX collagen is usually found in tissues containing type II collagen, a fibrillar collagen. Studies in knockout mice have shown that synthesis of the alpha 1 chain is essential for assembly of type IX collagen molecules, a heterotrimeric molecule, and that lack of type IX collagen is associated with early onset osteoarthritis. Mutations in this gene are associated with osteoarthritis in humans, with multiple epiphyseal dysplasia, 6, a form of chondrodysplasia, and with Stickler syndrome, a disease characterized by ophthalmic, orofacial, articular, and auditory defects. Two transcript variants that encode different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 6-70300398-A-G is Benign according to our data. Variant chr6-70300398-A-G is described in ClinVar as [Benign]. Clinvar id is 258362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-70300398-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.89-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000357250.11	NP_001842.3
COL9A1	NM_001377291.1	c.89-12T>C		splice_polypyrimidine_tract_variant, intron_variant			NP_001364220.1
COL9A1	XM_011535429.4	c.89-12T>C		splice_polypyrimidine_tract_variant, intron_variant			XP_011533731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.89-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001851.6	ENSP00000349790	P1
COL9A1	ENST00000370496.3	c.89-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000359527

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30603 AN: 151438 Hom.: 3336 Cov.: 31

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.190

GnomAD3 exomes AF: 0.168 AC: 42203 AN: 251072 Hom.: 4187 AF XY: 0.169 AC XY: 22986 AN XY: 135710

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.178 AC: 248179 AN: 1393150 Hom.: 23582 Cov.: 24 AF XY: 0.178 AC XY: 123949 AN XY: 697348

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.000712

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.201

Gnomad4 NFE exome AF: 0.185

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.202 AC: 30611 AN: 151542 Hom.: 3338 Cov.: 31 AF XY: 0.199 AC XY: 14754 AN XY: 74058

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.189

Alfa AF: 0.193 Hom.: 3220

Bravo AF: 0.202

Asia WGS AF: 0.0660 AC: 231 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0054
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12210123; hg19: chr6-71010101;